tbuckley/cabot-search huggingface dataset:
SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice
Authors: Kenneth H. Dinnon, Sarah R. Leist, Kenichi Okuda, Hong Dang, Ethan J. Fritch, Kendra L. Gully, Gabriela De la Cruz, Mia D. Evangelista, Takanori Asakura, Rodney C. Gilmore, Padraig Hawkins, Satoko Nakano, Ande West, Alexandra Schäfer, Lisa E. Gralinski, Jamie L. Everman, Satria P. Sajuthi, Mark R. Zweigart, Stephanie Dong, Jennifer McBride, Michelle R. Cooley, Jesse B. Hines, Miriya K. Love, Steve D. Groshong, Alison VanSchoiack, Stefan J. Phelan, Yan Liang, Tyler Hether, Michael Leon, Ross E. Zumwalt, Lisa M. Barton, Eric J. Duval, Sanjay Mukhopadhyay, Edana Stroberg, Alain Borczuk, Leigh B. Thorne, Muthu K. Sakthivel, Yueh Z. Lee, James S. Hagood, Jason R. Mock, Max A. Seibold, Wanda K. O’Neal, Stephanie A. Montgomery, Richard C. Boucher, Ralph S. Baric
Journal: Science Translational Medicine (2022)

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted SARS-CoV-2 strain MA10 produces an acute respiratory distress syndrome in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days after virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of profibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early antifibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.
PtoNF-YC9-SRMT-PtoRD26 module regulates the high saline tolerance of a triploid poplar
Authors: Shaofei Tong, Yubo Wang, Ningning Chen, Deyan Wang, Bao Liu, Weiwei Wang, Yang Chen, Jianquan Liu, Tao Ma, Yuanzhong Jiang
Journal: Genome biology (2022)

Sensing and responding to stresses determine the tolerance of plants to adverse environments. The triploid Chinese white poplar is widely cultivated in North China because of its adaptation to a wide range of habitats including highly saline ones. However, its triploid genome complicates any detailed investigation of the molecular mechanisms underlying its adaptations.We report a haplotype-resolved genome of this triploid poplar and characterize, using reverse genetics and biochemical approaches, a MYB gene, SALT RESPONSIVE MYB TRANSCRIPTION FACTOR (SRMT), which combines NUCLEAR FACTOR Y SUBUNIT C 9 (PtoNF-YC9) and RESPONSIVE TO DESICCATION 26 (PtoRD26), to regulate an ABA-dependent salt-stress response signaling. We reveal that the salt-inducible PtoRD26 is dependent on ABA signaling. We demonstrate that ABA or salt drives PtoNF-YC9 shuttling into the nucleus where it interacts with SRMT, resulting in the rapid expression of PtoRD26 which in turn directly regulates SRMT. This positive feedback loop of SRMT-PtoRD26 can rapidly amplify salt-stress signaling. Interference with either component of this regulatory module reduces the salt tolerance of this triploid poplar.Our findings reveal a novel ABA-dependent salt-responsive mechanism, which is mediated by the PtoNF-YC9-SRMT-PtoRD26 module that confers salt tolerance to this triploid poplar. These genes may therefore also serve as potential and important modification targets in breeding programs.
Idiopathic pleuroparenchymal fibroelastosis: three-dimensional computed tomography assessment of upper-lobe lung volume
Authors: Atsuki Fukada, Yuzo Suzuki, Kazutaka Mori, Masato Kono, Hirotsugu Hasegawa, Dai Hashimoto, Koshi Yokomura, Shiro Imokawa, Yuko Tanaka, Yusuke Inoue, Hironao Hozumi, Masato Karayama, Kazuki Furuhashi, Noriyuki Enomoto, Tomoyuki Fujisawa, Yutaro Nakamura, Naoki Inui, Yoshihisa Fujino, Hidenori Nakamura, Takafumi Suda
Journal: European Respiratory Journal (2022)

Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a rare interstitial lung disease characterised by predominant upper-lobe fibrosis involving the pleura and subpleural lung parenchyma. Despite its poor prognosis, there is no consensus on prognostic determinants of iPPFE to date. Because volume loss in the upper lobe is a distinct feature of iPPFE, we hypothesised that the lung volume of the bilateral upper lobes (upper-lobe volume) accurately indicates disease severity and mortality risk in iPPFE patients.This retrospective study assessed two cohorts of 132 patients with iPPFE (69 in Hamamatsu cohort; 63 in Seirei cohort) and 45 controls. Each lobe volume was quantitatively measured using three-dimensional computed tomography at the time of iPPFE diagnosis and standardised using predicted forced vital capacity.The standardised upper-lobe volume in iPPFE patients was less than half that of controls, whereas the lower-lobe volume did not decrease. iPPFE patients with lower standardised upper-lobe volume had significantly shorter survival rates than those with higher volume (median survival: 6.08 versus 2.48 years, p<0.001). In multivariate analysis, the lower standardised upper-lobe volume was significantly associated with increased mortality adjusting for age, sex and forced vital capacity (HR 0.939). A composite scoring model, including age, sex and standardised upper-lobe volume, better predicted risk of death than the gender-age-physiology model.Assessment of upper-lobe volume provides useful information for managing iPPFE by evaluating disease severity and mortality risk in clinical practice.
Promoting Nutrition Security Through Policies and Programs
Authors: Keith Churchwell, Stephanie Scarmo, Donald M. Lloyd-Jones
Journal: Circulation (2022)

s an important part of the mission to help people live longer, healthier lives, the American Heart Association (AHA) works to increase the likelihood that all people-particularly those most affected by social and economic disparities-have access to healthy and nutritious foods.An eating pattern rich in healthy nutrients and with appropriate caloric intake can promote healthy childhood development and learning as well as help people achieve and maintain good health throughout the life span.Conversely, food and nutrition insecurity leads to diets higher in calories, salt, and saturated fats and lower in fruits and vegetables, increasing risks for dysglycemia and obesity, all markers of poor cardiometabolic health.The term "food insecurity" refers to a household-level social or economic condition of limited access to sufficient food. 1 In 2020 (during the coronavirus disease 2019 [COVID-19] pandemic), 10.5% of US households reported being food insecure, with the rates of food insecurity higher for households with children; those with Black, non-Hispanic, and Hispanic household reference individuals; and those with incomes below 185% of the poverty threshold. 1US policies and programs that aim to improve food security have focused largely on ensuring that individuals have sufficient calories and quantities of food.Among advocates and experts, there is a growing consensus that a shift is needed to promote nutrition security, which means having equitable and stable availability of, access to, affordability of, and use of foods and beverages that promote wellbeing and prevent and treat disease. 2
Surgery at the End of Life—Aggressive But Necessary?
Authors: M. Andrew Millis, Pasithorn A. Suwanabol
Journal: JAMA Network Open (2022)

Anya L. Greenberg, MBA; Joseph A. Lin, MD, MPH; Alexis Colley, MD, MS; Emily Finlayson, MD, MS; Tasce Bongiovanni, MD, MPP; Elizabeth C. Wick, MD
Natural high-avidity T-cell receptor efficiently mediates regression of cancer/testis antigen 83 positive common solid cancers
Authors: Qingyang Li, Wei Hu, Baoyi Liao, Chanchan Song, Liangping Li
Journal: Journal for ImmunoTherapy of Cancer (2022)

T-cell receptor-engineered T cells (TCR-Ts) have achieved encouraging success in anticancer clinical trials. The antigenic targets, however, were primarily focused on human leukocyte antigen (HLA) A*02:01 restricted epitopes from a few cancer/testis antigens (CTAs) which are not widely expressed in common solid cancers; the tested T-cell receptors (TCRs) were frequently from tumor-infiltrating lymphocytes of old patients and were not assured to have higher avidity. Here, we propose the isolation of high-avidity TCRs against CTAs that are frequently expressed in common solid cancers.We selected the CT83 protein, which is frequently expressed in common solid cancers, as a model antigen for screening of its specific TCR. The predicted CT83 epitopes with strong or weak binding to HLA-I molecules, popular in the Chinese population, were integrated into three synthetic long peptides. CT83 reactive CD8+ T cells were stimulated with peptide-loaded dendritic cells (DCs) and sorted using the CD137 biomarker for single-cell sequencing to obtain the paired TCRαβ sequence. The higher frequency TCRs were reconstructed for characterization of the CT83 epitope and for assessment of in vitro and in vivo antitumor activities.CT83 reactive T cells from young healthy donors (YHDs) were generated by repeated stimulation with DCs and peptides. The single-cell TCR sequencing results of reactive T cells indicated that a single TCR clonotype dominated the paired TCRs. T cells engineered with this dominant TCR led to HLA-A*11:01-restricted recognition of the CT8314-22 epitope, with higher avidity. Functional assays showed powerful cytotoxicity in vitro against the targets of several CT83-positive solid cancer cell lines. Furthermore, TCR-Ts showed therapeutic efficacy in three xenograft solid tumor models. The meta-analysis of gene expression of 92 CTAs indicated that most CTAs did not or at low levels in the thymus, which suggested that those CTAs may experience incomplete thymic central tolerance.High-avidity TCR against CT83 could be isolated from YHDs and efficiently mediate regression of well-established xenograft common solid tumors. The high-avidity TCR repertoire in the peripheral blood of some donors for CT83 and other CTAs provides the basis for the efficient isolation of high-avidity TCRs to target numerous solid cancers.
Lipid-loaded macrophages as new therapeutic target in cancer
Authors: Giulia Marelli, Nicolò Morina, Federica Portale, Marta Pandini, Marta Iovino, Giusy Di Conza, Ping-Chih Ho, Diletta Di Mitri
Journal: Journal for ImmunoTherapy of Cancer (2022)

Abstract Macrophages are main players of the innate immune system. They show great heterogeneity and play diverse functions that include support to development, sustenance of tissue homeostasis and defense against infections. Dysfunctional macrophages have been described in multiple pathologies including cancer. Indeed tumor-associated macrophages (TAMs) are abundant in most tumors and sustain cancer growth, promote invasion and mediate immune evasion. Importantly, lipid metabolism influences macrophage activation and lipid accumulation confers pathogenic features on macrophages. Notably, a subset of lipid-loaded macrophages has been recently identified in many tumor types. Lipid-loaded TAMs support tumor growth and progression and exert immune-suppressive activities. In this review, we describe the role of lipid metabolism in macrophage activation in physiology and pathology and we discuss the impact of lipid accumulation in macrophages in the context of cancer.
Association of Allostatic Load With Overall Mortality Among Patients With Metastatic Non–Small Cell Lung Cancer
Authors: Samilia Obeng-Gyasi, Yaming Li, William E. Carson, Sarah Reisinger, Carolyn J. Presley, Peter G. Shields, David P. Carbone, DuyKhanh P. Ceppa, Ruth C. Carlos, Barbara L. Andersen
Journal: JAMA Network Open (2022)

Adverse social determinants of health (SDHs) (eg, poverty) are associated with poor oncologic outcomes among patients with lung cancer. However, no studies have evaluated biological correlates of adverse SDHs, operationalized as allostatic load (AL), with mortality due to lung cancer.To examine the association among AL, SDHs, and mortality among patients with metastatic non-small cell lung cancer (NSCLC).This cross-sectional study of an observational cohort was performed at a National Cancer Institute-designated comprehensive cancer center with data accrued from June 1, 2017, to August 31, 2019. Patients with metastatic (stage IV) NSCLC enrolled at diagnosis into a prospective observational cohort study were included in the present analysis if they had all the biomarkers to calculate an AL score (N = 143). Follow-up was completed on August 31, 2021, and data were analyzed from July 1 to September 30, 2021.Social determinants of health.Overall mortality and AL.A total of 143 patients met the study criteria with a median age of 63 (IQR, 55-71) years (89 men [62.2%] and 54 women [37.8%]). In terms of race and ethnicity, 1 patient (0.7%) was Asian, 7 (4.9%) were Black, 117 (81.8%) were White, 17 (11.9%) were of multiple races, and 1 (0.7%) was of other race or ethnicity. The mean (SD) AL was 2.90 (1.37). Elevated AL covaried with lower educational level (r = -0.26; P = .002), male sex (r = 0.19; P = .02), limited mobility (r = 0.19; P = .04), worsening self-care (r = 0.30; P < .001), problems engaging in usual activities (r = 0.21; P = .01), depressive symptoms (r = 0.23; P = .005), and a high number of stressful life events (r = 0.30; P < .001). Multivariable analysis found only increasing difficulty with mobility (r = 0.37 [95% CI, 0.13-0.60]; P = .002) and male sex (r = 0.63 [95% CI, 0.19-1.08]; P = .005) associated with higher AL. On adjusted analysis, elevated AL (hazard ratio, 1.43 [95% CI, 1.16-1.79]; P = .001) and low educational level (hazard ratio, 2.11 [95% CI, 1.03-4.34]; P = .04) were associated with worse overall mortality.The findings of this cross-sectional study suggest that higher AL was associated with adverse SDHs and worse overall mortality among patients with advanced NSCLC. These results provide a framework for replication and further studies of AL as a biological correlate for SDH and future prognostic marker.
Understanding Regional Mental Health Care–Seeking Behavior During the COVID-19 Pandemic—An Important Aspect of Addressing Resource Needs
Authors: Joseph A. Grubenhoff, Beau A. Carubia
Journal: JAMA Network Open (2022)

Natasha Ruth Saunders, MD, MSc; Therese A. Stukel, PhD; Rachel Strauss, MPH; Longdi Fu, MSc; Eyal Cohen, MD, MSc; Astrid Guttmann, MDCM, MSc; Alene Toulany, MD, MSc
Tom Nolan’s research reviews—7 July 2022
Authors: Tom Nolan
Journal: BMJ (2022)

<h3>Background</h3> Sub-Saharan Africa has high under-5 mortality and low childhood immunisation rates. Vaccine-preventable diseases cause one-third of under-5 deaths. Text messaging reminders improve immunisation completion in urban but not rural settings in sub-Saharan Africa. Low adult literacy may account for this difference. The feasibility and impact of combined automated voice and text reminders on immunisation completion in rural sub-Saharan Africa is unknown. <h3>Methods</h3> We randomised parturient women at the Mother and Child Hospitals Ondo State, Nigeria, owning a mobile phone and planning for child immunisation at these study sites to receive automated call and text immunisation reminders or standard care. We assessed the completion of the third pentavalent vaccine (Penta-3) at 18 weeks of age, immunisation completion at 12 months and within 1 week of recommended dates. We assessed selected demographic characteristics associated with completing immunisations at 12 months using a generalised binomial linear model with ‘log’ link function. Feasibility was assessed as proportion of reminders received. <h3>Results</h3> Each group had 300 mother−baby dyads with similar demographic characteristics. At 18 weeks, 257 (86%) and 244 (81%) (risk ratio (RR) 1.05, 95% CI 0.98 to 1.13; p=0.15) in the intervention and control groups received Penta-3 vaccine. At 12 months, 220 (74%) and 196 (66%) (RR 1.12, 95% CI 1.01 to 1.25; p=0.04) in the intervention and control groups received the measles vaccine. Infants in the intervention group were more likely to receive Penta-3 (84% vs 78%, RR 1.09, 95% CI 1.01 to 1.17; p=0.04), measles (73% vs 65%, RR 1.13, 95% CI 1.02 to 1.26; p=0.02) and all scheduled immunisations collectively (57% vs 47%, RR 1.13, 95% CI 1.02 to 1.26; p=0.01) within 1 week of the recommended date. No demographic character predicted immunisation completion. In the intervention group, 92% and 86% reported receiving a verification reminder and at least one reminder during the study period, respectively. <h3>Conclusion</h3> Paired automated call and text reminders significantly improved immunisation completion and timeliness. <h3>Trial registration number</h3> NCT02819895.
Two-age islet-autoantibody screening for childhood type 1 diabetes: a prospective cohort study
Authors: Mohamed Ghalwash, Jessica L Dunne, Markus Lundgren, Marian Rewers, Anette-G Ziegler, Vibha Anand, Jorma Toppari, Riitta Veijola, William Hagopian
Journal: The Lancet Diabetes & Endocrinology (2022)
Issues and Events
Journal: Diabetes Care (2022)

The American Diabetes Association is pleased to open the call for nominations for Pathway to Stop Diabetes awards.This call for nominations will prioritize translational applications that move knowledge and discovery gained from basic research to its eventual translation into patient and population benefit.The ideal applicant will propose innovative research that will be an important step toward the eventual goal of improving the lives of people at risk of diabetes or living with diabetes-and the pathway to this impact is clear.Applications are due by 1 August 2022.For more information, please visit professional.diabetes.org/content-page/current-funding-opportunities-pathway-stop-diabetes.
Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric <i>BRAFV600E</i> Brain Tumor Models
Authors: Fuyang Li, Kathryn M. Bondra, Samson Ghilu, Adam Studebaker, Qianqian Liu, Joel E. Michalek, Mari Kogiso, Xiao-Nan Li, John A. Kalapurakal, C. David James, Sandeep Burma, Raushan T. Kurmasheva, Peter J. Houghton
Journal: Clinical Cancer Research (2022)

Abstract Purpose: We investigated why three patient-derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both low-grade glioma (LGG) molecular subtypes. Experimental Design: Sensitivity to trametinib [MEK inhibitor (MEKi)] alone or in combination with rapamycin (TORC1 inhibitor), was evaluated in pediatric PDX models. The effect of combined treatment of trametinib with rapamycin on development of trametinib resistance in vivo was examined. PDX tissue and tumor cells from trametinib-resistant xenografts were characterized. Results: In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. In mice, acquired resistance to trametinib developed within three cycles of therapy in all three PDX models. Resistance to trametinib developed in situ is tumor-cell–intrinsic and the mechanism was tumor line specific. Rapamycin retarded or blocked development of resistance. Conclusions: In these three pediatric BRAF-mutant brain tumors, TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance, suggesting future therapeutic approaches using rapamycin analogs in combination with MEKis that may be therapeutically beneficial in both KIAA1549::BRAF- and BRAFV600E-driven gliomas.
Dietary modulation of gut microbiota in patients with colorectal cancer undergoing surgery: A review
Authors: José Ignacio Martínez-Montoro, María Antonia Martínez-Sánchez, Andrés Balaguer-Román, José Gil-Martínez, María José Mesa-López, Juan Egea-Valenzuela, Antonio José Ruiz-Alcaraz, María Isabel Queipo-Ortuño, Mercedes Ferrer, José Carlos Fernández-García, Bruno Ramos-Molina
Journal: International Journal of Surgery (2022)
Omicron SARS-CoV-2 Neutralization from Inactivated and ZF2001 Vaccines
Authors: Xin Zhao, Rong Zhang, Shitong Qiao, Xiao Wang, Weibing Zhang, Wenjing Ruan, Lianpan Dai, Pengcheng Han, George F Gao
Journal: New England Journal of Medicine (2022)